Interaction between a Novel Oligopeptide Fragment of the Human Neurotrophin Receptor TrkB Ectodomain D5 and the C-Terminal Fragment of Tetanus Neurotoxin
Candalija Iserte, Ana (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Scior, Thomas (Faculty of Chemical Sciences)
Rackwitz, Hans-Richard (Univerisity Campus (Alemanya))
Ruiz-Castelan, Jordan E. (Faculty of Chemical Sciences (Mèxic))
Martinez-Laguna, Ygnacio (Faculty of Chemical Sciences (Mèxic))
Aguilera, José (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)

Date:	2021
Abstract:	This article presents experimental evidence and computed molecular models of a potential interaction between receptor domain D5 of TrkB with the carboxyl-terminal domain of tetanus neurotoxin (Hc-TeNT). Computational simulations of a novel small cyclic oligopeptide are designed, synthesized, and tested for possible tetanus neurotoxin-D5 interaction. A hot spot of this protein-protein interaction is identified in analogy to the hitherto known crystal structures of the complex between neurotrophin and D5. Hc-TeNT activates the neurotrophin receptors, as well as its downstream signaling pathways, inducing neuroprotection in different stress cellular models. Based on these premises, we propose the Trk receptor family as potential proteic affinity receptors for TeNT. In vitro, Hc-TeNT binds to a synthetic TrkB-derived peptide and acts similar to an agonist ligand for TrkB, resulting in phosphorylation of the receptor. These properties are weakened by the mutagenesis of three residues of the predicted interaction region in Hc-TeNT. It also competes with Brain-derived neurotrophic factor, a native binder to human TrkB, for the binding to neural membranes, and for uptake in TrkB-positive vesicles. In addition, both molecules are located together in vivo at neuromuscular junctions and in motor neurons.
Grants:	Ministerio de Economía y Competitividad SAF2013-43900-R Agencia Estatal de Investigación SAF2016-80027-R
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Clostridium neurotoxins ; Neurotrophin receptors ; Carboxyl-terminal domain of tetanus neurotoxin ; Brain-derived neurotrophic factor
Published in:	Molecules, Vol. 26 (june 2021) , ISSN 1420-3049

DOI: 10.3390/molecules26133988
PMID: 34208805

23 p, 4.9 MB

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